Apparatus, method, and use for ultrasound mediated microbubble delivery of pharmaceutical compositions

Abstract

An apparatus, method, and use for ultrasound mediated microbubble delivery of pharmaceutical compositions to pulmonary tissue are provided. The pulmonary ultrasound apparatus includes an ultrasound signal generator for generating ultrasonic signals, an ultrasound transducer assembly having an ultrasound transducer operatively connected to the ultrasound signal generator, the ultrasound transducer configured to transmit the ultrasound signal generated by the ultrasound signal generator to pulmonary tissue, wherein the ultrasonic signal is transmitted at a frequency, a pressure, and a pulse duration for cavitating microbubbles to deliver a pharmaceutically active molecule to the pulmonary tissue.

What is claimed is: 
     
         1 . A pulmonary ultrasound apparatus comprising:
 an ultrasound signal generator for generating an ultrasonic signal;   an ultrasound transducer assembly having an ultrasound transducer operatively connected to the ultrasound signal generator, the ultrasound transducer configured to transmit the ultrasound signal generated by the ultrasound signal generator to pulmonary tissue;   wherein the ultrasonic signal is transmitted at a frequency, a pressure, and a pulse duration for cavitating microbubbles to deliver a pharmaceutically active molecule to the pulmonary tissue.   
     
     
         2 . The apparatus of  claim 1 , wherein the ultrasound transducer assembly has a flexible planar body for covering the at least part of the chest, and without movement of the ultrasound transducer assembly, the ultrasound transducer transmits the ultrasonic signal to the pulmonary tissue. 
     
     
         3 . The apparatus of  claim 1  or  2 , wherein the ultrasound transducer has a width and a length about the size of the intercostal muscles for transmitting the ultrasonic signal between the ribs. 
     
     
         4 . The apparatus of  claim 1  or  3 , wherein the ultrasound transducer assembly has an elongated body for endobronchial insertion, and the ultrasound transducer is at a distal end of the elongated body for transmitting the ultrasonic signal to the pulmonary tissue. 
     
     
         5 . The apparatus of any one of  claims 1  to  4 , wherein the ultrasound transducer directs targeted ultrasound signals to cavitate the microbubbles only when the microbubbles are detected in the pulmonary tissue. 
     
     
         6 . The apparatus of any one of  claims 1  to  5 , wherein the ultrasound transducer assembly has a movement mechanism for moving the ultrasound transducer assembly within the ultrasound transducer assembly. 
     
     
         7 . The apparatus of any one of  claims 1  to  6 , further comprising:
 an array of ultrasound transducers, the array of ultrasound transducer spaced apart a distance and each ultrasound transducer is operatively connected to the ultrasound signal generator. 
 
     
     
         8 . The apparatus of any one of  claims 1  to  6 , further comprising:
 a 2-dimensional array of ultrasound transducers, the array of ultrasound transducer spaced apart a first distance in a first dimension and a second distance in a second dimension, and each ultrasound transducer is operatively connected to the ultrasound signal generator. 
 
     
     
         9 . The apparatus of anyone of  claims 1  to  8 , wherein:
 the ultrasound transducer or the array of ultrasound transducers is capable of imaging, treating, or both imaging and treating an entire lung or both lungs entirely. 
 
     
     
         10 . The apparatus of claims any one of  claims 1  to  9 , wherein:
 the ultrasound transducer assembly is configured to maintain an adjustable spacing between the ultrasound transducers. 
 
     
     
         11 . An intravenous composition for treating pulmonary edema, the composition comprising:
 microbubbles;   a pharmaceutically active molecule; and   a pharmaceutically acceptable carrier.   
     
     
         12 . The composition of  claim 11 , wherein the pharmaceutically active molecule is at least one of microRNA, antagomir, and blockmir. 
     
     
         13 . The composition of  claim 12 , wherein the microRNA is at least one of miRNA-126, miRNA-150, miRNA-181b, miRNA126-3p, and miRNA150-5p; the antagomir is at least one of an antagomir to miRNA-27A and miRNA-146b; and the blockmir is at least one of a blockmir to miRNA-27A and miRNA-146b. 
     
     
         14 . The composition of  claim 11 , wherein the pharmaceutically active molecule is at least one of an aminoglycoside, steroid, antibiotic, vancomycin, antiviral, endothelial barrier-enhancing drug, and keratinocyte growth factor (KGF). 
     
     
         15 . The composition of  claim 14 , wherein the endothelial barrier-enhancing drug is one or more of vasculotide, adrenomedullin, fasudil, imatinib, atrial natriuretic peptide, and SIP. 
     
     
         16 . The composition of  claim 11 , comprising microRNA and at least one of an antibiotic compound and an antiviral compound. 
     
     
         17 . The composition of any one of  claims 11 - 16 , wherein the microbubble is coformulated with the pharmaceutically active compound. 
     
     
         18 . The composition of any one of  claims 11 - 17 , wherein the microbubble is formulated independently and added to a solution of pharmaceutically active compound. 
     
     
         19 . The composition of any one of  claims 11 - 18 , wherein the microbubble is bound to the pharmaceutically active compound. 
     
     
         20 . Use of pulmonary ultrasound to treat pulmonary edema comprising:
 providing an intravenous composition to a patient comprising a plurality of microbubbles, a pharmaceutically active compound, and a pharmaceutically acceptable carrier; and   applying ultrasound to the patient at a target of pulmonary edema to cavitate the microbubbles and deliver the pharmaceutically active compound to the patient.   
     
     
         21 . The use of  claim 20 , wherein the pharmaceutically active molecule is at least one of a microRNA, antagomir, and blockmir. 
     
     
         22 . The use of  claim 21 , wherein the microRNA is one or more of miRNA-126, miRNA-150, miRNA-181b, miRNA126-3p, and miRNA150-5p; the antagomir is at least one of an antagomir to miRNA-27A and miRNA-146b; and the blockmir is at least one of a blockmir to miRNA-27A and miRNA-146b. 
     
     
         23 . The use of  claim 20 , wherein the pharmaceutically active molecule is at least one of an aminoglycoside, antibiotic, steroid, vancomycin, antiviral, endothelial barrier-enhancing drug, and keratinocyte growth factor (KGF). 
     
     
         24 . The use of  claim 23 , wherein the endothelial barrier-enhancing drug is one or more of vasculotide, adrenomedullin, fasudil, imatinib, atrial natriuretic peptide, and SIP. 
     
     
         25 . The use of  claim 20 , wherein the intravenous composition comprises microRNA and at least one of an antibiotic compound and an antiviral compound. 
     
     
         26 . A method of treating pulmonary edema, the method comprising:
 administering intravenously to a patient:
 microbubbles; and 
 a pharmaceutically active molecule; and 
   irradiating the patient with ultrasound at a target of pulmonary edema to deliver the pharmaceutically active compound to the patient.   
     
     
         27 . The method of  claim 26 , wherein the pulmonary edema is associated with acute respiratory distress syndrome. 
     
     
         28 . The method of  claim 26 , wherein the pulmonary edema is associated with cystic fibrosis. 
     
     
         29 . The method of  claim 26 , wherein the pulmonary edema is associated with congestive heart failure. 
     
     
         30 . The method of any one of  claims 26 - 29 , wherein the pharmaceutically active molecule is one or more of microRNA, an aminoglycoside, vancomycin, antiviral, endothelial barrier-enhancing drug, and keratinocyte growth factor (KGF). 
     
     
         31 . The method of any one of  claims 26 - 30 , wherein the microbubbles and the pharmaceutically active molecule are delivered to the patient simultaneously. 
     
     
         32 . The method of any one of  claims 26 - 30 , wherein the microbubbles and the pharmaceutically active molecule are delivered to the patient sequentially. 
     
     
         33 . The method of any one of  claims 26 - 32 , wherein the target of pulmonary edema is lung endothelium lining. 
     
     
         34 . A method for delivering a pharmaceutical active molecule to a site of pulmonary edema, comprising:
 introducing microbubbles to an area proximate to the site of pulmonary edema; and   directing an ultrasonic signal to the site of pulmonary edema, the ultrasonic signal for cavitating the microbubbles to deliver the pharmaceutically active molecule to the site of pulmonary edema.   
     
     
         35 . The method of  claim 34 , further comprising:
 scanning a chest cavity to identify internal structures including one or more organs, site of pulmonary edema, injured lung tissue, and healthy lung tissue.   
     
     
         36 . The method of  claim 34  or  35 , further comprising:
 scanning the site of pulmonary edema for echogenicity changes in the injured lung tissue after delivery of the pharmaceutically active molecule to the site of pulmonary edema. 
 
     
     
         37 . The method of any one of  claims 34  to  36 , further comprising:
 detecting whether microbubbles are in the area proximate to the site of pulmonary edema. 
 
     
     
         38 . The method of any one of  claims 34  to  37 , further comprising:
 directing an ultrasonic signal to the site of pulmonary edema, the ultrasonic signal for cavitating the microbubbles, only when the microbubbles are detected in the area proximate to the site of pulmonary edema.